Transcription Factor HIF-1 Is a Necessary Mediator of the Pasteur Effect in Mammalian Cells

Abstract

The ability to respond to differential levels of oxygen is important to all respiring cells. The response to oxygen deficiency, or hypoxia, takes many forms and ranges from systemic adaptations to those that are cell autonomous. Perhaps the most ancient of the cell-autonomous adaptations to hypoxia is a metabolic one: the Pasteur effect, which includes decreased oxidative phosphorylation and an increase in anaerobic fermentation. Because anaerobic fermentation produces far less ATP than oxidative phosphorylation per molecule of glucose, increased activity of the glycolytic pathway is necessary to maintain free ATP levels in the hypoxic cell. Here, we present genetic and biochemical evidence that, in mammalian cells, this metabolic switch is regulated by the transcription factor HIF-1. As a result, cells lacking HIF-1␣ exhibit decreased growth rates during hypoxia, as well as decreased levels of lactic acid production and decreased acidosis. We show that this decrease in glycolytic capacity results in dramatically lowered free ATP levels in HIF-1␣-deficient hypoxic cells. Thus, HIF-1 activation is an essential control element of the metabolic state during hypoxia; this requirement has important implications for the regulation of cell growth during development, angiogenesis, and vascular injury.Decreased environmental oxygen forces cells and tissues to adapt in multiple ways. In response to hypoxia, a significant number of changes in gene expression occur, resulting in elevated transcription of angiogenic factors, hematopoietic factors, and some metabolic enzymes (21). The switch between the two forms of respiration utilized by animal cells, aerobic versus anaerobic, was first noted by Pasteur in the late 19th century (12,22). As the oxygen level decreases, the generation of ATP shifts from the oxidative phosphorylation pathway in the mitochondria to the oxygen-independent pathway of glycolysis in the cytoplasm. Although glycolysis is less efficient than oxidative phosphorylation in the generation of ATP, in the presence of sufficient glucose glycolysis can sustain ATP production due to increases in the activity of the glycolytic enzymes (12,22). Perhaps nowhere has this forced adaptation been the focus of so much study as in transformed cells; this is because in solid tumors it is clear that a large percentage of the cell population is at least transiently hypoxic (1).Earlier in the 20th century, Otto Warburg demonstrated that tumors differed from normal tissues in their utilization of the glycolytic pathway (26). For a given amount of glucose, tumor fragments ex vivo produced far more lactate than sections of nontransformed tissues under normoxic conditions. In vivo the situation is likely to be more complex. Within individual tumors, there are some areas that may respond to hypoxia by exhibiting the normal physiological switch to glycolysis similar to that employed by all nontransformed cells in response to lowered oxygen levels. Concurrently, many other areas of transformed cells in solid tumors may adapt to h...

Erythropoietin as an antiapoptotic, tissue-protective cytokine

“…The induction of glycolytic enzymes demonstrates a role for HIF in the metabolic, cell-autonomous adaptation to hypoxia represented by the switch of ATP generation from oxidative phosphorylation to glycolysis, the Pasteur effect. 4 It has also been suggested that, because HIF is often constitutively expressed in tumors, it may mediate the high constitutive expression of glycolytic enzymes that is the basis of the Warburg effect. 3,5 The metabolic changes induced by hypoxia clearly play a role in ischemic preconditioning, a well-known phenomenon, reported for various organs including the heart, brain, kidney and liver, whereby pre-exposure to hypoxia (such as a minor ischemic event) protects from subsequent, severe ischemia.…”

The role of autophagy in the heart

“…[72][73][74] Although HIF-1a has multiple mechanisms to protect the heart, 75 one of the most significant mechanisms particularly relevant for protecting the heart against ischemia/reperfusion could be its effects on cardiac metabolism. 75 Activation of endogenous HIF-1a stimulates the glycolytic pathway 76 and inhibits the TCA cycle 77 and fatty acid oxidation, 78,79 which is beneficial for preserving ATP and reducing O 2 consumption during ischemia/reperfusion. 80 Interestingly, HIF-1a stimulates mitochondrial autophagy through upregulation of Bnip3 in mouse embryo fibroblasts.…”

Role for casein kinase 2 in the regulation of HIF‐1 activity

“…In addition to promoting VEGF release, HIF-1 is also essential for tumor cell adaptation to hypoxia, notably via increasing glycolysis capacity. 6 HIF-1 is a heterodimeric transcription factor composed of 2 members of the basic helix-loop-helix (bHLH) proteins containing Per-ARNT-Sim (PAS) motif, HIF-1a and ARNT (aryl receptor nuclear translocator). 7 HIF-1a is the subunit regulated by hypoxia and the oxygen-dependent regulation occurs at multiple levels in vivo.…”